Abstract 188: Selective Inhibition of Vascular Smooth Muscle Cell Migration by Targeting Plasminogen Activator Inhibitor-1

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Neha Goyal ◽  
Zhen Weng ◽  
Philip Fish ◽  
Tammy Strawn ◽  
Samantha Myears ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Cell Migration ◽  
Plasminogen Activator ◽  
Intimal Hyperplasia ◽  
Differential Effect ◽  
Plasminogen Activator Inhibitor ◽  
Dependent Manner ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

Introduction: Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of mammalian plasminogen activators and an important regulator of cell migration. We have shown that tiplaxtinin, a small molecule, specific inhibitor of PAI-1, inhibits intimal hyperplasia in a murine vein graft model. However, little is known about the effects of pharmacological inhibition of PAI-1 on vascular cell migration under physiologically relevant conditions. Methods: We studied the effects of tiplaxtinin on migration of smooth muscle cells (SMCs) and endothelial cells (ECs). Results: Tiplaxtinin significantly inhibited migration of murine SMCs through 3-dimensional (3-D) collagen matrix in a concentration-dependent manner. Tiplaxtinin did not inhibit SMC proliferation, and it did not inhibit migration of PAI-1-deficient SMCs, suggesting that tiplaxtinin’s effect on SMCs was non-toxic and PAI-1-dependent. The anti-migratory effect of tiplaxtinin on SMCs was preserved in collagen 3-D matrix containing vitronectin and other extracellular matrix molecules, further supporting the physiological significance of the effect. In contrast to SMCs, tiplaxtinin did not inhibit migration of human aortic ECs in vitro or murine ECs in vivo, the latter assessed in a murine carotid injury model. To study the basis for the differential effect of tiplaxtinin on SMCs vs. ECs, we compared expression of LDL receptor-related protein 1 (LRP1), a motogenic receptor for PAI-1, between cell types by RT-PCR and found that LRP1 gene expression was significantly lower in ECs than in SMCs. Furthermore, recombinant PAI-1 stimulated the migration of wild-type mouse embryonic fibroblasts (MEFs), but not LRP1-deficient MEFs. Conclusions: Tiplaxtinin, a pharmacological inhibitor of PAI-1, inhibits SMC migration under physiological conditions, while having no inhibitory effect on EC migration. The differential effect of PAI-1 inhibition on SMCs vs. ECs appears to be mediated by LRP1 and may be of clinical significance, as it is advantageous to prevent intimal hyperplasia by inhibiting SMC migration without inhibiting EC migration, which is key to preserving an intact, anti-thrombotic vascular endothelium.

The alkylating carcinogen N-methyl-N’-nitro-N-nitrosoguanidine activates the plasminogen activator inhibitor-1 gene through sequential phosphorylation of p53 by ATM and ATR kinases

2005 ◽  
Vol 93 (03) ◽  
pp. 584-591 ◽  
Author(s):  
Mercè Jardí ◽  
Shin'ichi Saito ◽  
Ettore Appella ◽  
Berta Vidal ◽  
Maribel Parra ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Dependent Manner ◽  
Plasminogen Activator Inhibitor 1 ◽  
Environmental Carcinogen ◽  
Atr Kinases ◽  
Activator Inhibitor ◽  
Pai 1

SummaryThe alkylating agent MNNG is an environmental carcinogen that causes DNA lesions leading to cell death. We previously demonstrated that MNNG induced the transcriptional activity of the plasminogen activator inhibitor-1 (PAI-1) gene in a p53-dependent manner. However, the mechanism(s) linking external MNNG stimulation and PAI-1 gene induction remained to be elucidated. Here, we show that ATM and ATR kinases, but not DNA-PK, which participate in DNA damage-activated checkpoints, regulate the phosphorylation of p53 at serine 15 in response to MNNG cell treatment. Using ATM-deficient cells, ATM was shown to be required for early phosphorylation of serine 15 in response to MNNG, whereas catalytically inactive ATR selectively interfered with late phase serine 15 phosphorylation. In contrast, DNA-PK-deficient cells showed no change in the MNNG-induced serine 15 phosphorylation pattern. In agreement with this, sequential activation of ATM and ATR kinases was also required for adequate induction of the endogenous PAI-1 gene by MNNG. Finally, we showed that cells derived from PAI-1-deficient mice were more resistant to MNNG-induced cell death than normal cells, suggesting that p53-dependent PAI-1 expression partially mediated this effect. Since PAI-1 is involved in the control of tumor invasiveness, our finding that MNNG induces PAI-1 gene expression via ATM/ATR-mediated phosphorylation of p53 sheds new insight on the role of these DNA damage-induced cell cycle checkpoint kinases.

scholarly journals Expression of plasminogen activator-inhibitor-1 (PAI-1) during cellular remodeling in proliferative glomerulonephritis in the rat.

1995 ◽  
Vol 43 (9) ◽  
pp. 895-905 ◽  
Author(s):  
J L Barnes ◽  
R J Mitchell ◽  
E S Torres
Keyword(s):  
Extracellular Matrix ◽  
Cell Migration ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Proliferative Glomerulonephritis ◽  
Plasminogen Activator Inhibitor 1 ◽  
Glomerular Lesions ◽  
Matrix Accumulation ◽  
Activator Inhibitor ◽  
Pai 1

Pericellular proteolysis involves the plasminogen activator/plasmin system and plays an important role in cell remodeling involving cell migration and extracellular matrix turnover. Studies in this laboratory have previously characterized a model of proliferative glomerulonephritis induced by Habu snake venom (HSV) in the rat that involves cell migration, proliferation, and extracellular matrix accumulation. Because plasminogen activator-inhibitor-1 (PAI-1) has been used as a marker for cell migration as well as matrix accumulation, we were interested in examining the temporal and spatial expression and cellular sources of PAI-1 mRNA and translated protein over the course of HSV-induced proliferative glomerulonephritis. The results showed a highly localized and progressive expression of PAI-1 mRNA and translated protein by in situ hybridization and immunohistochemistry at the margins and periphery of glomerular lesions 8 and 24 hr after HSV. The expression of PAI-1 in glomerular lesions localized to the same sites as mesangial cell marker proteins, desmin and Thy-1.1, indicating that mesangial cells synthesize this important regulator proteolysis. Few cells expressed PAI-1 in the central aspects of glomerular lesions at later time intervals (48 and 72 hr) when cell proliferation and expression of extracellular matrix (fibronectin protein and mRNA) were maximal. Therefore, the expression of PAI-1 in this model was associated more with early events related to cell migration than with proliferation or extracellular matrix synthesis. These observations support the hypothesis that the plasminogen activator/plasmin system is involved in cell migration in early remodeling during glomerular disease.

Induction of plasminogen activator inhibitor 1 by the PPARα ligand, Wy-14,643, is dependent on ERK1/2 signaling pathway

2003 ◽  
Vol 90 (10) ◽  
pp. 611-619 ◽  
Author(s):  
Cristina Banfi ◽  
Johan Auwerx ◽  
Federica Poma ◽  
Elena Tremoli ◽  
Luciana Mussoni
Keyword(s):  
Plasminogen Activator ◽  
Signaling Pathway ◽  
Plasminogen Activator Inhibitor ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Plasminogen Activator Inhibitor 1 ◽  
Luciferase Reporter Construct ◽  
Pparγ Agonist ◽  
Activator Inhibitor ◽  
Pai 1

SummaryImpairment of the fibrinolytic system, mostly due to elevated plasma levels of plasminogen activator inhibitor 1 (PAI-1), is often associated with metabolic disorders such as diabetes mellitus and insulin-resistance syndrome. Moreover, insulin, as we have previously shown, directly stimulates PAI-1 production with a mechanism underlying a complex signaling network which ultimately leads to ERK activation.In this study we have analyzed the effects of agonists of the per-oxisome proliferator-activated receptor (PPAR) alpha and gamma on PAI-1 biosynthesis in HepG2 cells in the presence or absence of insulin. The high affinity PPARα agonist, Wy-14,643, increased basal and insulin-stimulated PAI-1 antigen release with a mechanism involving gene transcription. We then investigated whether the MAP kinase pathway also plays a role in the stimulatory properties of Wy-L4,643. Wy-L4,643 increases phosphorylation of ERK and p38 in a time-dependent manner without affecting that of SAPK/JNK or ERK5. Moreover, the MEK (ERK kinase) inhibitors, PD98059 and UO126, completely prevented PAI-1 induction by Wy-14,643 without inhibiting the activation of a reporter gene carrying the PPRE element. Interestingly, the addition of p38 inhibitor followed by insulin and Wy-14,643 resulted in a greater than additive stimulation of PAI-1 secretion acting through ERK1/2 phosphorylation.In contrast, the synthetic PPARγ agonist, rosiglitazone, did not change PAI-1 level, although this compound induced transcription from the PPRE-driven luciferase reporter construct.In conclusion, Wy-14,643 induces PAI-1 gene expression, in the presence or absence of insulin, with a mechanism which is independent on PPARα activation and requires signaling through the ERK1/2 signaling pathway.

scholarly journals Combined but not single treatment with ethinylestradiol/levonorgestrel and spironolactone reduces plasminogen activator inhibitor-1 in insulin-resistant ovariectomised rats

2019 ◽  
Vol 20 (4) ◽  
pp. 147032031989593
Author(s):  
Adeyanju Oluwaseun Aremu ◽  
Dibia Chinaza Lilian ◽  
Soladoye Ayodele Olufemi ◽  
Olatunji Lawrence Aderemi
Keyword(s):  
Plasminogen Activator ◽  
Density Lipoprotein ◽  
Plasminogen Activator Inhibitor ◽  
Dependent Manner ◽  
Model Assessment ◽  
Plasminogen Activator Inhibitor 1 ◽  
Insulin Resistant ◽  
Ovx Rats ◽  
Activator Inhibitor ◽  
Pai 1

Objective: Increased circulating level of plasminogen activator inhibitor-1 (PAI-1) is associated with menopausal oestrogen deficiency. We therefore hypothesised that the combined oral contraceptive (COC) with spironolactone (SPL) improves insulin resistance (IR) in ovariectomised (OVX) rats by reducing circulating PAI-1. Methods: Twelve-week-old female Wistar rats were divided into sham-operated (SHM), OVX, OVX+SPL (0.25 mg/kg), COC (1.0 µg ethinylestradiol and 5.0 µg levonorgestrel) and OVX+COC+SPL rats treated with COC and SPL daily for eight weeks. IR was assessed by homeostatic model assessment of IR (HOMA-IR). Results: Data showed that OVX rats had a higher HOMA-IR value that is associated with increased visceral adiposity, triglycerides (TG), total cholesterol/high-density lipoprotein cholesterol (HDL-C), TG/HDL-C, plasma insulin, GSK-3, corticosterone and decreased 17β-oestradiol. However, these effects were attenuated in OVX+COC, OVX+SPL and OVX+COC+SPL rats compared to OVX rats. OVX rats had lower PAI-1 than SHM rats, whereas the beneficial effect on IR and other parameters by COC or SPL was accompanied with increased PAI-1. Improvement of IR and other parameters with combined COC and SPL in OVX rats was accompanied with reduced PAI-1. Conclusion: Taken together, COC or SPL improves IR independent of PAI-1, whereas a combination of COC and SPL in OVX rats ameliorates IR in a PAI-1-dependent manner.

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